This grant is a response to PA-99-049 and addresses three topics listed as research objectives. The topics include: item 13, Genetic, cellular and biochemical basis for functional senescence: item 16, Nutrient modulation: and item 18, Animal models of aging. California mice are a novel model of type II diabetes mellitus that can be used to elucidate dietary and genetic determinants of disease occurrence and progression that are relevant to the human disease The California mouse (Peromyscus californicus) is a desert rodent closely related to the white-footed deer mouse (Peromyscus leucopus), a commonly used aging model. We have determined that susceptible California mice become diabetic if fed a moderately high fat commercial mouse breeder diet. Diabetic mice have hyperlipidemia, hyperinsulinemia, hyperglycemia and islet cell pathology. California mice fed a lower fat commercial rodent chow do not manifest as many metabolic abnormalities as animals fed the high fat diet, but may become hyperinsulinemic and have hyperplasia of pancreatic islet cells. We have conducted longitudinal studies that have identified populations of mice that are relatively more susceptible or resistant to the deleterious effects of a high fat diet. These longitudinal studies also indicate that hyperlipidemia precedes hyperglycemia in these mice. We mated animals with high triglyceride responses to high fat feeding with other high-responding mice. Low-responding mice were also mated with each other. Our test matings of susceptible and resistant California mice indicate that the hyperlipidemia phenotype in the parents is inherited in the offspring. Some California mice also become obese when fed the high fat diet. Our proposed research seeks to determine the mechanism by which the hyperlipidemia and obesity develop over time in populations of diabetes susceptible and resistant animals. We will establish selectively bred lines of diabetes resistant and diabetes susceptible California mice and we will use these selectively bred lines to determine whether hypertriglyceridemia in California mice is caused by increased secretion of lipid into the circulation or decreased lipoprotein catabolism by lipoprotein lipase. We will also determine how changes in body composition affect the occurrence of diabetes. The proposed research will also establish a source of selectively bred diabetes susceptible and diabetes resistant California mice as a genetic resource for other investigators.